From the Department of (Neuro)Pathology, Academic Medical Center (AMI, JvS, JJA, EA), and Swammerdam Institute for Life Sciences, Center for Neuroscience (EA), University of Amsterdam, Amsterdam; and Stichting Epilepsie Instellingen Nederland, Heemstede (EA), the Netherlands; Institute of Neurology, Medical University of Vienna, Vienna, Austria (IM, GGK); and Inserm UMR 676, Physiopathology and Neuroprotection of the Developing Brain, Robert Debré Hospital, Paris, France (HA-B).
J Neuropathol Exp Neurol. 2014 Jul;73(7):671-83. doi: 10.1097/NEN.0000000000000083.
The mammalian target of rapamycin (mTOR) signaling pathway is a key developmental pathway involved in mechanisms underlying cellular aging and neurodegeneration. We hypothesized that its deregulation may occur during early brain development in patients with Down syndrome (DS). The expression patterns and cellular distribution of components of mTOR signaling (phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR) were investigated in developing hippocampi from controls and patients with DS and from adults with DS and Alzheimer disease-associated pathology using immunocytochemistry. In control hippocampi, only phosphorylated S6 was detected prenatally (19-41 gestational weeks); it became undetectable 2 months postnatally. Increased expression of phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR was observed in DS hippocampus compared with controls. Phosphorylated S6 and phosphorylated S6 kinase were detected prenatally and persisted throughout postnatal development. Prominent expression of mTOR components was observed in pyramidal neurons with granulovacuolar degeneration and in neurons containing neurofibrillary tangles in the hippocampi of DS subjects with Alzheimer disease pathology. These findings suggest that a dysregulated mTOR pathway may contribute to both early hippocampal developmental abnormalities and hippocampal functional impairment developing before neurodegeneration. Moreover, the expression patterns of mTOR components in adult DS hippocampus support its association with Alzheimer disease-related histopathologic changes.
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路是一个关键的发育途径，涉及细胞衰老和神经退行性变的机制。我们假设，其失调可能发生在唐氏综合征（DS）患者的早期大脑发育过程中。我们使用免疫细胞化学技术研究了来自对照组和 DS 患者以及来自具有 DS 和阿尔茨海默病相关病理学的成年人的发育中海马中 mTOR 信号（磷酸化 S6、磷酸化 S6 激酶、磷酸化真核起始因子 4E 结合蛋白 1 和磷酸化 mTOR）的表达模式和细胞分布。在对照组海马体中，仅在产前（19-41 孕周）检测到磷酸化 S6；出生后 2 个月检测不到。与对照组相比，DS 海马体中观察到磷酸化 S6、磷酸化 S6 激酶、磷酸化真核起始因子 4E 结合蛋白 1 和磷酸化 mTOR 的表达增加。磷酸化 S6 和磷酸化 S6 激酶在产前检测到，并在出生后发育过程中持续存在。在具有颗粒空泡变性的锥体神经元和含有神经原纤维缠结的神经元中观察到 mTOR 成分的明显表达，这些神经元存在于具有阿尔茨海默病病理学的 DS 患者的海马体中。这些发现表明，失调的 mTOR 途径可能导致早期海马体发育异常和神经退行性变之前的海马体功能障碍。此外，成年 DS 海马体中 mTOR 成分的表达模式支持其与阿尔茨海默病相关组织病理学变化的关联。
